Systemic lupus erythematosus (SLE) is an autoimmune disease affecting over 1 million Americans, mostly women, which is influenced by both genetic and environmental risk factors and shortens the life span. Its clinical features include glomerulonephritis, cardiovascular disease (CVD), skin rashes, serositis, hemolytic anemia, impairment of the central nervous system and bone loss. Several animal models are in use to study SLE including NZB x NZW F1 (B/W) and MRL/lpr mice. We have demonstrated that ad libitum (AL) food intake with n-6 fatty acids (corn oil) enriched in 18:2 linoleic acid (LA) promotes rapid development of SLE in both strains of mice including bone loss in MRL/lpr mice. Although feeding AL a regular fish oil containing 22- 30% EPA/DHA (20:5 + 22:6) n-3 fatty acids provides some benefit, calorie restriction (CR) alone significantly delayed the onset of the disease. We recently noted, however, that concentrated fish oil (EPA/DHA 50%) when fed AL protects against kidney disease similar to CR. Concentrated n-3 fatty acid (FA) supplementation was able to inhibit the increase in NF-kB, and co-stimulatory molecules, and increase antioxidant enzymes in target tissues resulting in a decrease of proinflammatory IL-18 cytokine. We now hypothesize that recently available through prescription, OMACOR fish oil (EPA/DHA 90%), to treat hyperglyceridemic patients, will reduce pro-inflammatory cytokines from macrophages and T cells, thereby preventing or delaying the onset of autoimmune disease. The proposed new studies in specific aim 1 is to establish the minimal dose of OMACOR fish oil required to suppress renal disease and prolong maximal lifespan in B/W and MRL/lpr mice; Specific aim 2 is to determine the changes in anti- and pro-inflammatory cytokines, NF-kB expression and other signaling pathways in macrophages and T cells of B/W and MRL/lpr mice fed OMACOR fish oil; Specific aim 3 is to determine the interaction of OMACOR n-3 fatty acids along with immunosuppressive cyclophosphamide and methylprednisolone drug therapy after the onset of SLE in controlling renal disease and bone loss in MRL/lpr mice. These new studies with FDA approved OMACOR n-3 FA will establish its efficacy against renal disease and bone loss alone, or in combination with immunosuppressive drugs. The proposed studies will also help to gain insight to undertake clinical studies to prevent renal and CVD as well as bone loss in SLE patients.